Specific JNK inhibition by D-JNKI1 protects Purkinje cells from cell death in Lurcher mutant mouse.
In the Lurcher mutant mouse (+/Lc), Purkinje cells (PCs) selectively die due to the mutation that converts alanine to threonine in the glutamate ionotropic receptor GRID 2, thus resulting in a constitutively leaky cation channel. This intrinsic cell death determines a target-dependent cell death of granule cells and olivary neurons and cerebellum cytoarchitecture is severely disrupted in the adult Lurcher mutant. Although the +/Lc mutant has been widely characterized, less is known about the molecules involved in +/Lc PC death. We, here, used organotypic cerebellar slice cultures from P0 mice to investigate the role of c-jun N-terminal kinase (JNK) in +/Lc PC death by using D-JNKI1 as very specific tool to inhibit its action. Our results showed that D-JNKI1 treatment increased the number of +/Lc PC at 14 DIV of 3.6-fold. Conversely, this specific JNK inhibitor cell permeable peptide did not increase PC number in +/+ treated versus untreated cultures. These results clearly indicate that JNK plays an important role in +/Lc PC mechanism of cell death.
Repici
Mariaelena
M
Centre National de la Recherche Scientifique, UMR7102-Neurobiologie des Processus Adaptatifs, Paris, France.
Zanjani
Hadi S
HS
Gautheron
Vanessa
V
Borsello
Tiziana
T
Dusart
Isabelle
I
Mariani
Jean
J
D000409:Alanine / Q000235:genetics; D019943:Amino Acid Substitution; D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death; D002463:Cell Membrane Permeability; D002531:Cerebellum / Q000166:cytology* / Q000473:pathology; D003433:Crosses, Genetic; D005260:Female; D005838:Genotype; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants / Q000502:physiology*; D009154:Mutation; D009474:Neurons / Q000201:enzymology / Q000502:physiology; D010455:Peptides / Q000502:physiology*; D011689:Purkinje Cells / Q000166:cytology; D017470:Receptors, Glutamate / Q000235:genetics*; D013912:Threonine / Q000235:genetics
D010455:Peptides; D017470:Receptors, Glutamate; C107913:glutamate receptor delta 2; D013912:Threonine; D048670:MAP Kinase Kinase 4; C478085:D-JNKI-1; D000409:Alanine